Hafezi-Moghadam Ali, Simoncini Tommaso, Yang Zequan, Limbourg Florian P, Plumier Jean-Christophe, Rebsamen Michael C, Hsieh Chung-Ming, Chui Dao-Shan, Thomas Kennard L, Prorock Alyson J, Laubach Victor E, Moskowitz Michael A, French Brent A, Ley Klaus, Liao James K
The Center for Blood Research, Harvard Medical School, Boston, Massachusetts, USA.
Nat Med. 2002 May;8(5):473-9. doi: 10.1038/nm0502-473.
Corticosteroids have been shown to exert beneficial effects in the treatment of acute myocardial infarction, but the precise mechanisms underlying their protective effects are unknown. Here we show that high-dose corticosteroids exert cardiovascular protection through a novel mechanism involving the rapid, non-transcriptional activation of endothelial nitric oxide synthase (eNOS). Binding of corticosteroids to the glucocorticoid receptor (GR) stimulated phosphatidylinositol 3-kinase and protein kinase Akt, leading to eNOS activation and nitric oxide dependent vasorelaxation. Acute administration of pharmacological concentrations of corticosteroids in mice led to decreased vascular inflammation and reduced myocardial infarct size following ischemia and reperfusion injury. These beneficial effects of corticosteroids were abolished by GR antagonists or eNOS inhibitors in wild-type mice and were completely absent in eNOS-deficient (Nos3(-/-)) mice. The rapid activation of eNOS by the non-nuclear actions of GR, therefore, represents an important cardiovascular protective effect of acute high-dose corticosteroid therapy.
皮质类固醇已被证明在急性心肌梗死的治疗中发挥有益作用，但其保护作用的具体机制尚不清楚。在此我们表明，高剂量皮质类固醇通过一种涉及内皮型一氧化氮合酶（eNOS）快速非转录激活的新机制发挥心血管保护作用。皮质类固醇与糖皮质激素受体（GR）结合刺激磷脂酰肌醇3激酶和蛋白激酶Akt，导致eNOS激活和一氧化氮依赖性血管舒张。在小鼠中急性给予药理浓度的皮质类固醇导致血管炎症减轻，并且在缺血再灌注损伤后心肌梗死面积减小。在野生型小鼠中，GR拮抗剂或eNOS抑制剂消除了皮质类固醇的这些有益作用，而在eNOS缺陷（Nos3(-/-)）小鼠中则完全不存在这些作用。因此，GR的非核作用对eNOS的快速激活代表了急性高剂量皮质类固醇治疗的重要心血管保护作用。
